The pharmacokinetics of iloprost were studied in 12 hospitalized patients suffering from severe peripheral arterial occlusive disease (PAOD) stages III or IV according to Fontaine. The patients were 8 males and 4 females aged from 49 to 83 years. Apart from PAOD, several other concomitant diseases were present, e.g. myocardial and/or renal insufficiency, diabetes and hypertension. Patients were treated daily with i.v. infusions of iloprost at dosages of 1.0-3.3 ng/kg/min over a period of 4 to 6 h. Dose-normalized steady-state plasma levels ranged from 39 to 100 pg/ml (65 +/- 20 pg/ml). The total clearance accounted for 16 +/- 5 ml/min/kg. Post-infusion disposition in the plasma was biphasic with half-lives of 4 +/- 2 min and 37 +/- 8 min. The plasma level profiles obtained on days 4 and 14 of treatment in 3 patients were similar. Sex specific kinetic differences were not observed. In comparison to healthy volunteers, studied in an earlier trial, total clearance was slightly lower and consequently steady state levels were increased (p less than 0.05) in PAOD patients. Half-lives in the plasma were not significantly different.
Summary Disease characteristics. Several hundred genes are known to cause hereditary hearing loss and deafness. The hearing loss may be conductive, sensorineural, or a combination of both; syndromic or nonsyndromic; and prelingual (before language develops) or postlingual (after language develops). Diagnosis/testing. Genetic forms of hearing loss must be distinguished from acquired (non-genetic) causes of hearing loss. The genetic forms of hearing loss are diagnosed by otologic, audiologic, and physical examination, family history, ancillary testing (such as CT examination of the temporal bone), and molecular genetic testing. Molecular genetic tests are available for many types of syndromic and nonsyndromic deafness, often only on a research basis. On a clinical basis, molecular genetic testing is available for the diagnosis of branchiootorenal (BOR) syndrome (EYA1 gene), Mohr-Tranebjaerg syndrome (deafnessdystonia-optic atrophy syndrome; TIMM8A gene), Pendred syndrome (SLC26A4 gene), Usher syndrome type 2A (USH2A gene), Usher syndrome type 3 (one mutation in USH3A), DFNA3 and DFNB1 (GJB2 and GJB6 genes), DFN3 (POU3F4 gene), DFNB4 (SLC26A4 gene), DFNA6/14 (WFS1 gene), DFNA8/12, DFNB9 (OTOF gene), and DFNB21 (TECTA gene). Testing for deafness-causing mutations in the GJB2 gene (which encodes the protein connexin 26) and GJB6 (which encodes the protein connexin 30) plays a prominent role in diagnosis and genetic counseling. Management. Hereditary hearing loss is managed by a team including an otolaryngologist, an audiologist, a clinical geneticist, and a pediatrician, and sometimes an educator of the Deaf, a neurologist, and a pediatric ophthalmologist. Treatment includes hearing aids and vibrotactile devices; cochlear implantation is considered in children over
Abstract MLKL is the essential effector of necroptosis, a form of programmed lytic cell death. We have isolated a mouse strain with a single missense mutation, Mlkl D139V , that alters the two-helix ‘brace’ that connects the killer four-helix bundle and regulatory pseudokinase domains. This confers constitutive, RIPK3 independent killing activity to MLKL. Homozygous mutant mice develop lethal postnatal inflammation of the salivary glands and mediastinum. The normal embryonic development of Mlkl D139V homozygotes until birth, and the absence of any overt phenotype in heterozygotes provides important in vivo precedent for the capacity of cells to clear activated MLKL. These observations offer an important insight into the potential disease-modulating roles of three common human MLKL polymorphisms that encode amino acid substitutions within or adjacent to the brace region. Compound heterozygosity of these variants is found at up to 12-fold the expected frequency in patients that suffer from a pediatric autoinflammatory disease, chronic recurrent multifocal osteomyelitis (CRMO).
AbstractIloprost is a chemically stable, pharmacologically highly potent PGl2-mimetic for which therapeutic efficacy was proven after iv infusion treatment in PAOD-patients. The development of an oral, therapy facilitating preparation was mainly based on the imitation of plasma levels as obtained after iv to provide an equieffective dosage form. Due to the short half-life in plasma a modified release preparation was formulated. In the present set of experiments the pharmacokinetics of sustained release iloprost in animals and man was investigated after species specifically different dosages. After normalization for the bioavailable fraction of a 150 μg dose several mean pharmacokinetic parameters were similar in all species with peak plasma levels of 162, 223 and 160 pg/ml (pig, dog, man), tmax-values of 1.5, 1.9 and 1.6 h, AUC-values of 651, 730 and 763 pg-h/ml. The half-value duration, representing the time of half-maximal plasma levels and thus describing retardation, accounted for 2.8, 2.5 and 2.4 h. For all species a correlation between in-vitro liberation data of the dosage form and drug amount absorbed in-vivo could be shown. Despite differences in gastrointestinal conditions pharmacokinetics was able to demonstrate an interspecies comparability of systemic iloprost levels after intragastric treatment with an extended release preparation of iloprost, which helped to select an optimal formulation variant and to extrapolate toxicological tolerability data for the administration to man. By this strategy a promising oral dosage form could be selected which might be therapeutically equivalent to iv infusion after individual dose titration in patients.
Objective To understand the etiological landscape and phenotypic differences between 2 developmental and epileptic encephalopathy (DEE) syndromes: DEE with spike–wave activation in sleep (DEE‐SWAS) and epileptic encephalopathy with spike–wave activation in sleep (EE‐SWAS). Methods All patients fulfilled International League Against Epilepsy (ILAE) DEE‐SWAS or EE‐SWAS criteria with a Core cohort (n = 91) drawn from our Epilepsy Genetics research program, together with 10 etiologically solved patients referred by collaborators in the Expanded cohort (n = 101). Detailed phenotyping and analysis of molecular genetic results were performed. We compared the phenotypic features of individuals with DEE‐SWAS and EE‐SWAS. Brain‐specific gene co‐expression analysis was performed for D/EE‐SWAS genes. Results We identified the etiology in 42/91 (46%) patients in our Core cohort, including 29/44 (66%) with DEE‐SWAS and 13/47 (28%) with EE‐SWAS. A genetic etiology was identified in 31/91 (34%). D/EE‐SWAS genes were highly co‐expressed in brain, highlighting the importance of channelopathies and transcriptional regulators. Structural etiologies were found in 12/91 (13%) individuals. We identified 10 novel D/EE‐SWAS genes with a range of functions: ATP1A2 , CACNA1A , FOXP1 , GRIN1 , KCNMA1 , KCNQ3 , PPFIA3 , PUF60 , SETD1B, and ZBTB18 , and 2 novel copy number variants, 17p11.2 duplication and 5q22 deletion. Although developmental regression patterns were similar in both syndromes, DEE‐SWAS was associated with a longer duration of epilepsy and poorer intellectual outcome than EE‐SWAS. Interpretation DEE‐SWAS and EE‐SWAS have highly heterogeneous genetic and structural etiologies. Phenotypic analysis highlights valuable clinical differences between DEE‐SWAS and EE‐SWAS which inform clinical care and prognostic counseling. Our etiological findings pave the way for the development of precision therapies. ANN NEUROL 2024;96:932–943
Pathogenic variants in DDX3X have recently been identified to be a relatively common cause of intellectual disability in females. In this study, we describe six female probands, from five unrelated families, with five novel heterozygous variants in DDX3X , and the identification of potential germline mosaicism. Consistent features between this cohort and previously described cases include developmental delay or intellectual disability, growth disturbance and movement disorder. Common facial dysmorphism within the cohort include short palpebral fissures, micrognathia, bulbous nasal tip, protruding ears, high arched palate, thin upper vermillion and smooth philtrum. Novel clinical features identified from this cohort include facial dysmorphisms, perinatal complications, valgus feet deformity, lipoatrophy, dystonic episodes, and cutaneous mastocytosis. This case series attempts to expand the phenotype of the DDX3X syndrome; however, it remains heterogeneous. Description of further cases is required to more accurately identify the significance of novel phenotypes within this cohort.
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